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Blood, 1 June 2004, Vol. 103, No. 11, pp. 4084-4092.
Prepublished online as a Blood First Edition Paper on February 12, 2004; DOI 10.1182/blood-2003-06-1827.
Submitted June 6, 2003
Accepted January 29, 2004
The role of apoptosis in the development of AGM hematopoietic stem cells revealed by Bcl-2 overexpression
Claudia Orelio, Kirsty N Harvey, Colin Miles, Robert A Oostendorp, Karin van der Horn, and Elaine Dzierzak*
Cell Biology and Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands
International Centre for Life, Institute of Human Genetics, Newcastle-upon-Tyne, United Kingdom
Labor fur Stammzellphysiologie, Technische Universitat Munchen, Munchen, Germany
* Corresponding author; email: e.dzierzak{at}erasmusmc.nl.
Apoptosis is an essential process in embryonic tissue remodeling and adult tissue homeostasis. Within the adult hematopoietic system, it allows for tight regulation of hematopoietic cell subsets. Previously, it was shown that Bcl-2 overexpression in the adult increases the viability and activity of hematopoietic cells under normal and/or stressful conditions. However, a role for apoptosis in the embryonic hematopoietic system has not yet been established. Since the first hematopoietic stem cells (HSC) are generated within the aorta-gonad-mesonephros region (AGM; an actively remodeling tissue) beginning at embryonic day 10.5, we examined this tissue for expression of apoptosis-related genes and ongoing apoptosis. Here, we show expression of several pro- and anti-apoptotic genes in the AGM. We also generated transgenic mice overexpressing Bcl-2 under the control of the transcriptional regulatory elements of the HSC marker Sca-1, to test for the role of cell survival in the regulation of AGM HSCs. We provide evidence for increased numbers and viability of Sca-1 positive cells in the AGM and subdissected midgestation aortas, the site where HSCs are localized. Most importantly, our in vivo transplantation data show that Bcl-2 overexpression increases AGM and fetal liver HSC activity, strongly suggesting that apoptosis plays a role in HSC development.
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